GMF-dependent neuroinflammation and neurodegeneration

GMF 依赖性神经炎症和神经变性

• 批准号: 8666674
• 负责人: ASGAR ZAHEER
• 金额: $ 32.7万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666674
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Adenoviruses; Affect; Age; American; Animal Model; Astrocytes; Autopsy; Behavioral; Brain; Cultured Cells; Development; Diagnosis; Disease; Experimental Animal Model; Exposure to; Gender; Glia Maturation Factor; Goals; Human; Human Pathology; In Vitro; Inflammation; Inflammation Mediators; Investigation; Knock-out; Knockout Mice; Laboratories; Lentivirus Vector; Lewy Bodies; Maintenance; Mediator of activation protein; Messenger RNA; Microglia; Molecular Profiling; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Normal tissue morphology; Parkinson Disease; Pathogenesis; Pathology; Production; Proteins; Reactive Nitrogen Species; Reactive Oxygen Species; Research; Resistance; Role; Side; Signal Transduction; Small Interfering RNA; Stimulus; Techniques; Testing; Therapeutic Intervention; Time; Transfection; Treatment Efficacy; Wild Type Mouse; base; brain cell; brain tissue; chemokine; comparative; cytokine; disorder control; dopaminergic neuron; effective therapy; fetal; motor deficit; mouse model; nervous system disorder; neurochemistry; neuroinflammation; neuron loss; neurotoxic; novel; novel therapeutic intervention; overexpression; pollutant; prevent; research study; small hairpin RNA

DESCRIPTION (provided by applicant): Parkinson's disease is progressive disabling and fatal. It is estimated that 60,000 new cases are diagnosed each year, joining the 1 million Americans who currently have Parkinson's disease, and there is no cure for this disease. PD is characterized by the presence of degenerating dopaminergic neurons, Lewy bodies and activated glia in brain. Although, the cause of PD is not clear, exposure to environmental neurotoxic pollutant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to be associated with the pathology of human PD and in animal models of PD. Invariably, activated glia are not only present but are also persistent in PD brains which could facilitate maintenance and progression of PD by secreting deleterious cytokines and chemokines. The glia maturation factor (GMF), discovered and characterized in our laboratory, is a conserved protein in mammalian brain/central nervous system. We already demonstrated the prominent role of GMF in activation of astrocytes and microglia by various factors and stimuli leading to death of neuronal cells. We hypothesize that GMF is also involved in pathogenesis of PD. This novel hypothesis is based on the demonstrated functions of GMF and our recent immuno-histological examinations that revealed numerous activated astrocytes, microglia and the prominence of GMF in nigrostriatal region of postmortem PD brains, as well as, in brains of experimental animal model of PD in which the changes in GMF, astrocytes and microglia preceded the loss of dopamine neurons. We forward three specific aims to support our hypothesis. Specific Aim 1 will examine the association between GMF and the pathology of PD. We will also examine whether GMF-dependent glial activation is required in the production of proinflammatory mediators that are responsible for degeneration of dopaminergic neurons. Specific Aim 2 will chart the comparative pathogenesis and progression of MPTP-induced dopaminergic neuronal loss in GMF-containing wild type and in GMF-deficient (GMF-KO) mice. We will compare the histopathological features, neurochemical changes, and behavioral motor deficits in Wt mice with GMF-KO mice. Specific Aim 3 will evaluate the suppression of neuroinflammation/neurodegeneration and therapeutic efficacy of our novel therapeutic approach of targeting GMF with GMF-specific siRNA to silence the GMF-signaling in MPTP-intoxicated mice.

描述（由申请人提供）：帕金森病是一种进行性致残和致命的疾病。据估计，每年有6万例新病例被诊断出来，加入目前患有帕金森病的100万美国人的行列，这种疾病没有治愈方法。PD的特征是脑内存在变性的多巴胺能神经元、路易体和活化的胶质细胞。虽然PD的病因尚不清楚，但已知暴露于环境神经毒性污染物1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）与人类PD和PD动物模型的病理学相关。帕金森病患者脑内不仅存在活化的胶质细胞，而且这些胶质细胞通过分泌有害的细胞因子和趋化因子促进帕金森病的维持和进展。胶质成熟因子（glia maturation factor，GMF）是本实验室发现并鉴定的一种哺乳动物脑/中枢神经系统的保守蛋白。我们已经证明了GMF在各种因素和刺激导致神经元细胞死亡的星形胶质细胞和小胶质细胞活化中的突出作用。我们推测转基因食品也参与了PD的发病机制。这一新的假说是基于GMF的功能和我们最近的免疫组织学检查，发现许多活化的星形胶质细胞，小胶质细胞和突出的GMF在死后PD脑的黑质纹状体区域，以及在PD的实验动物模型的大脑中，其中GMF，星形胶质细胞和小胶质细胞的变化先于多巴胺神经元的损失。我们提出了三个具体的目标来支持我们的假设。具体目标1将检查GMF和PD病理之间的关联。我们还将研究是否需要GMF依赖的神经胶质细胞激活的促炎介质，负责多巴胺能神经元的变性的生产。具体目标2将在含有GMF的野生型和GMF缺陷（GMF-KO）小鼠中比较MPTP诱导的多巴胺能神经元损失的发病机制和进展。我们将比较Wt小鼠和GMF-KO小鼠的组织病理学特征、神经化学变化和行为运动缺陷。具体目标3将评估神经炎症/神经变性的抑制和我们用GMF特异性siRNA靶向GMF以沉默MPTP中毒小鼠中的GMF信号传导的新治疗方法的治疗功效。